Process of producing primary delta-alkenyl malonic esters



Patented Nov. 19, 1940 UNlTED STATES PATENT OFFME PROCESS OF PRODUCINGPRIMARY A1- ALKENYL MALONIC ESTERS Arthur C. Cope, Bryn Mawr,

Incorporated, Philadelphia,

Sharp & Dohme,

Pa., assignor to Pa., a corporation of Maryland '7 Claims.

This invention relates to a new process for the production of primaryni-alkenyl alkyl malonic and cyanoacetic esters. It relates moreparticularly to a process for the conversion of primary alkylidenemalonic and cyanoacetic esters into the corresponding alkyl m-alkenylesters.

The products which are produced by this novel process, the primaryA1alkenyl alkyl malonic esters and cyanoacetic esters, are valuable asintermediates for the production of corresponding primary Al-alkenylalkyl thiobarbituric acids and barbituric acids, and also for theproduction of unsaturated monobasic acids, which may be prepared by thede-carboxylation of the malonic esters or by the removal of the nitrilegroup from the cyanoacetic esters.

In accordance with the process of the present invention, the primaryalkylidene malonic esters or cyanoacetic esters are alkylated by meansof an alkylating agent, such as an alkyl sulfate, halide, or other alkylsalt, in an inert solvent in the presence of metallic sodium. Apparentlythe metallic sodium reacts with the primary alkylidene compound toproduce a sodioderivative, which in turn reacts with the alkyl salt,with the elimination of an inorganic sodium salt, and the production ofthe desired primary Al-alkenyl alkyl ester. In the course of thereaction, the double bond uniting the cyanoacetic or the malonic esterradical with the alkylidene radical is shifted to the A1 position in thealkenyl group, so that the alkylidene group is changed to a A1-alkeny1group, and the alkyl group of the alkylating agent becomes attached tothe methylene carbon of the malonic or cyanoacetic ester. As thereaction is carried out with metallic sodium in an inert solvent, sidereactions are minimized, and the reaction proceeds smoothly, and withgood yields.

In carrying out the process, any available primary alkylidene malonicester or cyanoacetic ester may be used. The primary alkylidene compoundsmay be prepared advantageously by the condensation of the correspondingaldehydes with malonic ester or cyanoacetic ester in the presence or" asuitable condensing agent, such as a soluble salt, such as piperideneacetate, as described in my copending application Serial No. 105,825,filed October 15, 1936. Other methods of preparing these primaryalkylidene esters may be used, of course, but the process described inmy said prior application is of particular advantage, inasmuch as it isapplicable to the production of the alkylidene esters from any availablealdehyde, and enables a wide range of the primary alkylidene esters tobe prepared.

The invention will be further illustrated by the following specificexample, but it is not limited thereto. 5

EmampZe.--ll.5 parts of sodium are powdered under Xylene and rinsed intoa suitable reaction vessel equipped with a mechanical stirrer, a refluxcondenser, and a dropping funnel, with 350 parts of dry ether. Thevessel is cooled in an 10 ice bath while 107 parts of n-butylidenemalonic ester is added, with stirring, over a period of 10 minutes. Theresulting solution (the sodio derivative of the ester is formed slowlyis refluxed for about 6 hours, after which 85 parts 5 of diethyl sulfateare added over a period of 10 minutes, and the refluxing is continuedfor another 24 hours. The n-butylidene malonic ester and sodium are usedin about equal molar proportions, and the alkylating agent, the diethylsulfate, is used in an amount somewhat in excess of equal molarproportions. After the reaction mixture has refluxed for about 24 hours,it is acidified with dilute hydrochloric acid, the ethereal layer isremoved, and the aqueous layer 25 is extracted with ether. The ethereallayer and extract are combined, and the ether removed by evaporation atreduced pressure. The residue is then shaken for about 24 hours withaqueous ammonia to remove any unalkylated material, and the desiredester is extracted from the ammonia with ether, washed with water, anddistilled. The resulting product ethyl nA1-butenyl malonic ester, boilsat 104-107 C./2-3 mm.

The ethyl sulfate used in the above example may be replaced by anequivalent amount of any other alkyl sulfate, or alkyl halide, or otheralkyl salts, with the introduction of corresponding alkyl groups intothe final product. If alkyl halides are used, it is advantageous to usethe bromides or the iodides, as these are somewhat more reactive thanthe chlorides, and increase the efiiciency of the reaction.

Similarly, in place of the n-butylidene malonic ester, other primaryalkylidene malonic esters, such as n-propylidene, isobutylidene,n-pentylidene, citronellylidene, and other malonic esters may be used asall of the primary alkylidene malonic esters, or aralkylidene malonicesters, react in an analogous manner.

The primary alkylidene and aralkylidene cyanoacetic esters may bealkylated by a procedure similar to that outlined in the example, withthe use of metallic sodium in an inert solvent, and, as an alkylatingagent, an alkyl salt, such as an alkyl halide or sulfate. Some of theprimary alkylidene cyanoacetic esters tend to polymerize, in contrast tothe corresponding primary alkylidene malonic esters, Which are quitestable. In such cases it is advantageous to employ the more stablealkylidene malom'c esters.

Various inert solvents, i. e., solvents which do not react with thesodium or other reactants, may be used, including such solvents as dryether, benzene, toluene, etc. In general, the solvent most advantageousfor the production of a given primary A1alkenyl malonic or cyanoaceticester is the solvent in which the intermediate sodium derivative is themost soluble. Thus, for some products, ether is the best solvent,whereas for others, benzene or toluene may give better results. Otherinert solvents may also-be used, and particularly solvents in which theintermediate sodium derivatives are relatively soluble.

. Sodamide may be used in place of the metallic sodium, in an inertsolvent, with about the same high conversion; but, if sodamide is used,it must be handled with due precautions, as, if not properly handled, itis explosive. One way in which it may be used safely involves dissolvingit in liquid ammonia, admixing the solution with an inert solvent, suchas benzene, ether or the like, and removing the liquid ammonia byvaporization. The inert solvent, containing the sodamide, may then beused in the process.

Among the primary A1-alkenyl malonic and cyanoacetic esters which may bereadily prepared by the process, with good yields, and with aminimum ofundesirable side reactions, are the following:

n-Propyl nl-n-propenyl malonic ester Ethyl ni-n-butenyl malonic estern-Propyl nl-n-butenyl malonic ester Isopropyl A1-n-butenyl malonic esterAllyl ni-n-butenyl malonic ester Ethyl ni-iso-butenyl malonic esterMethyl A1-nheptenyl malonio ester Ethyl isobutenyl cyanoacetic esterAllyl nl-n-butenyl cyanoacetic ester Isopropyl ni-n-butenyl oyanoaceticester Ethyl nl-n-heptenyl cyano-acetic ester Methyl ni-n-pentenylcyanoacetic ester It will thus be seen that by the present invention, Iprovide a novel and advantageous process for the production of primaryni-alkenyl lalkyl malonic esters and cyanoacetic esters, by the.alkylation of the corresponding primary alkylidene malonic orcyanoacetic ester, With'the production of the desired product with highyields and in a condition such that it can be readily purified andisolated.

I claim:

l. The process of preparing esters of primary ni-alkenyl alkyl malonicacids which comprises reacting a primary alkylidene malonic ester with asubstance of the class consisting of metallic sodium and sodamide in aninert solvent, and replacing the sodium in the resultingsodio-derivative with an alkyl group by means of an alkyl salt.

2. lhe process of producing esters of primary ni-alkenyl alkyl malonicacids which comprises reacting an alkyl halide with a primary alkylidenemalonio ester in the presence of metallic sodium in an inert solvent.

3. The process of producing esters of primary nl-alkenyl alkyl malonicacids which comprises reacting an alkyl sulfate with a primaryalkylidene malonic ester in the presence of metallic sodium in an inertsolvent.

l. The process of producing esters of primary nl-alkenyl alkyl malonicacids which comprises reacting an alkyl salt with a primary alkylidenemalonic ester in the presence of metallic sodium in an inert solvent.

5. The process of A1-all enyl alkyl malonic acids which comprisesreacting an alkyl salt with a primary alkylidene malonic ester in thepresence of a substance of the class consisting of metallic sodium andsodamide in ether.

6. The process of producing esters of primary ni-alkenyl alkyl malonicacids which comprises reacting an alkyl salt with a primary alkylidenemalonic ester in the presence of a substance of the class consisting ofmetallic sodium and sodamide in benzene.

7. The process of producing esters of primary nl-alkenyl alkyl malonicacids which comprises reacting an alkyl salt with a primary alkylidenemalonic ester in the presence of a substance of the class consisting ofmetallic sodium and sodamide in toluene.

ARTHUR C. COPE.

producing esters of primary

